Medicines and medicinal kits

ABSTRACT

It is intended to provide medicines having a higher ocular tension-lowering effect on ocular hypertension and glaucoma. Because of showing an excellent effect of lowering ocular tension, medicines comprising a combination of a prostaglandin compound with an NO-donating compound are useful in treating ocular hypertension and glaucoma.

TECHNICAL FIELD

[0001] The present invention relates to a medicine comprising a mixtureof a prostaglandin compound and a nitric oxide (hereinafter referred toas “NO”) donating compound that is effective in the treatment of ocularhypertension and glaucoma.

BACKGROUND ART

[0002] Presently, eye drop solutions and internal medicines areprincipally used for reducing ocular tension in the treatment of ocularhypertension and glaucoma. As examples of eye drop solutions, β-blockerssuch as timolol maleate, carteolol hydrochloride, befunololhydrochloride, and betaxolol hydrochloride, sympathetic nerve stimulantssuch as epinephrine and dipivefrine hydrochloride, parasympathetic nervestimulants such as pilocarpine hydrochloride and carbachol, α-blockerssuch as bunazosin, αβ-blockers such as nipradilol, and prostaglandinderivatives such as isopropyl unoprostone and latanoprost can be given.As examples of internal medicines, carbonic anhydrase inhibitors such asacetazolamide, methazolamide, and diclofenamide can be given.

[0003] In many cases, the use of only one of these medicines cannotsufficiently control ocular tension. Therefore, the combined use of twoor more of these medicines has increased. However,there are cases wherethe combined use of these medicines does not significantly reduce oculartension, thereby making the selection of these medicines very difficult.

[0004] Accordingly, an object of the present invention is to provide amedicine that significantly reduces ocular tension resulting from ocularhypertension and glaucoma, in particular, a medicine that effectivelyreduces ocular tension in cases where the combined use of conventionalmedicines is not effective.

DISCLOSURE OF THE INVENTION

[0005] To achieve the above object, the present inventors have conductedextensive research of a medicine comprising a prostaglandin compound anda NO-donating compound.

[0006] Of the above medicines, prostaglandin compounds are already knownto be effective in reducing ocular tension when used alone. However, theaction mechanism of this effect has not yet been fully understood. It iscommonly believed that this effect is due to the increased uveoscleralflow rate and there are several opinions regarding the reason. Oneopinion is that prostaglandin F₂α causes secretion of MMP. MMP degradesthe extracellular matrix of the smooth muscle fibers of the ciliary body(uveoscleral outflow pathway) thereby decreasing outflow resistance andincreasing outflow (Lutjen-Drecoll E. and Tamm E., Exp. Eye. Res 47,761-769, 1988). Another opinion is that the smooth muscle fibers of theciliary body become relaxed and the cell spacing expands therebydecreasing outflow resistance and increasing outflow (Poyer J F. , Inv.Opht. Vis. Sci. 36, 2461-2465, 1995).

[0007] The inventors of the present invention paid particular attentionto the following reports on prostaglandin. As a result of combining aprostaglandin compound (a derivative of prostaglandin F₂α. inparticular) with a prostaglandin receptor, phospholipase A₂ isstimulated, thereby causing arachidonic acid to be produced and releasedfrom the biomembrane phospholipid. This arachidonic acid is convertedinto prostaglandin G₂ by the action of cyclooxygenase then convertedinto various types of endogenic prostaglandin. In this instance,prostaglandin E₂ and prostaglandin F₂α are produced and cause theciliary muscle to become relaxed thereby increasing the uveoscleral flowrate, and as a result, the ocular tension is reduced (Y. K. Sardar, Exp.Eye. Res. 63, 305, 1996 and the like)

[0008] The ocular tension reducing effect of NO donating compounds hasalready been known in the art. The nitric oxide released by the NOdonating compound activates the guanylate cyclase, which increases theamount of cyclic GMP (S. A. Waldman et al, J. Biol. Chem 259, 5946,1984), and results in reduced ocular tension (J. A. Nathanson et al,Invest. Ophthal. Vis. Sci. Abstr. 29, 323, 1988).

[0009] In general, the combination of several components effective inreducing ocular tension does not greatly improve the overall effect.However, the inventors of the present invention conducted research basedon the assumption that a mixture of a prostaglandin compound and an NOdonating compound could significantly reduce ocular tension, wherein thenitric oxide released by the NO donating compound not only activatesguanylate cyclase but also activates cycloxygenase (D. Salvemini, et al,Proc. Natl. Acad. Sci. USA 90, 7240, 1993) thereby enhancing theconversion of arachidonic acid in the ocular tension reducing mechanismof the prostaglandin compound. As a result, the inventors havediscovered that this combination is in fact highly effective in reducingocular tension, thereby completing the present invention.

[0010] Accordingly, the present invention provides a medicine comprisinga prostaglandin compound and an NO donating compound.

[0011] The present invention also provides a method for treating and/orpreventing ocular hypertension or glaucoma using the above medicine.

[0012] Since ocular hypertension and glaucoma can be very difficult totreat, there are many cases where these disorders cannot be completelycured using conventional medicines for reducing ocular tension.Experimented use of various combinations of these medicines, whichresulted in either no improvement or only a slight improvement ineffect, could not achieve a significant improvement in the treatment ofthese disorders.

[0013] In the medicine of the present invention comprising thecombination of a prostaglandin compound and an NO donating compound, thenitric oxide is released from the NO donating compound and enhances theconversion of the arachidonic acid in the ocular tension reducingmechanism of the prostaglandin compound, thereby exhibiting asynergistic effect of the two compounds of significantly increasing theocular tension reducing effect. Thus, the medicine is not only effectivein regular ocular hypertension and glaucoma patients but is alsoeffective in those patients wherein the combined use of severalconventional medicines does not significantly reduce ocular tension.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0014] As the prostaglandin compound used in the medicine of the presentinvention, all pharmaceutically acceptable prostaglandin compounds,derivatives, and analogues thereof can be given, wherein the derivativesinclude pharmaceutically acceptable esters and salts thereof.

[0015] As examples of the prostaglandin compound, naturally occurringprostaglandins such as prostagladin (hereinafter referred to as “PG”)D₁, PGE₁, PGE₂, PGE₃, PGF₁α, PGF₂α, PGF₃α, PGG₂, PGH₂, PGI₂, and PGI₃,thromboxane A₂, latanoprost, isopropyl unoprostone, PGF₂α 1-isopropylester, salt of PGF₂α 1-isopropyl ester-15-propione, and 15-deoxy PGF₂αcan be given without any limitations. These prostaglandin compounds maybe used singularly or in combination of two or more.

[0016] Of those given above, prostaglandin F₂α derivatives arepreferably used as the prostaglandin compound in the medicine of thepresent invention, with PGF₂α, latonoprost, and isopropyl unoprostenebeing particularly preferable.

[0017] In the medicine of the present invention, the prostaglandincompound is preferably used in an amount of 0.0001-0.05 w/v %, andparticular preferably 0.001-0.01 w/v % of the total amount of thecompound.

[0018] As the NO donating compound used in the medicine of the presentinvention, those that release NO (nitric oxide) in vivo can be given.Examples of the NO donating compound include, but are not limited to,nipradilol, nitroglycerine, isosorbide dinitrate, sodium nitroprusside,N-nitrosoacetyl penicillamine, 3-morpholino-sydnonimine hydrochloride,S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitrosoglutathione,4-phenyl-3-furoxanecarbonitryl, arginine, and sodium nitrite. These NOdonating compounds may be used singularly or in combination of two ormore.

[0019] Of the above NO donating compounds, nipradilol is particularlypreferable. In addition to releasing NO, nipradilol is known to beeffective in α,β blocking, which adds an increased effect to thetreatment of ocular hypertension and glaucoma.

[0020] In the medicine of the present invention, the NO donatingcompound is preferably used in an amount of 0.01-5 w/v %, and particularpreferably 0.1-1.0 w/v % of the total amount of the compound.

[0021] The medicine of the present invention may be used in the form ofan eye drop solution and the like, wherein the prostaglandin and NOdonating compounds may be combined into a single preparation or eachcompound may be separate preparations and administered in order in theform of a medicine kit or the like.

[0022] In the medicine of the present invention, the use of a singlepreparation comprising both compounds is advantageous in view ofconvenience. On the other hand, the use of each compound in separatepreparations is also advantageous because the method of administrationcan be determined and the amount of each compound administered can becontrolled.

[0023] The medicine of the present invention is preferably used in theform of an eye drop solution. This eye drop solution may comprise theprostaglandin compound and the NO donating compound in separatecontainers or both the prostaglandin compound and NO donating compoundin the same container.

[0024] In the preparation of the above medicine, commonly used basematerials, dissolution agents, solubilizers, solvents, wetting agents,emulsifiers, excipient, adhesives, viscous agents, binders,preservatives, antioxidants, stabilizers, surfactants, antiseptics, pHadjustors, and the like may be appropriately used in accordance with theform of the preparation.

EXAMPLES

[0025] The present invention will be described in more detail by the wayof examples, which should not be construed as limiting the presentinvention.

Example 1

[0026] 100 ml of an aqueous solution containing 0.25 w/v % of nipradiloland 100 ml of an aqueous solution containing 0.005 w/v % of latonoprostwere prepared separately and combined into a single package to prepare amedicine kit.

Example 2

[0027] 100 ml of an aqueous solution containing 0.1 w/v % of sodiumnitroprusside and 100 ml of an aqueous solution containing 0.005 w/v %of latonoprost were prepared separately and combined into a singlepackage to prepare a medicine kit.

Examples 3 and 4

[0028] The medicines of Examples 3 and 4 were prepared using theingredients and amounts shown in Table 1. TABLE 1 Example 3 Example 4nipradilol  0.25 g nitroprusside  0.10 g Na latanoprost 0.005 glatanoprost 0.005 g purified appropriate amount purified waterappropriate amount water total amount   100 mL total amount   100 mL

Test Example 1

[0029] Domesticated rabbits intravenously administered with 100 μl of a5 w/v % hypertonic saline solution were used as ocular hypertensionmodels. After intravenously administering the hypertonic salinesolution, 50 μl of each of the eye drop solutions were administered andthe ocular tension was measured 60 and 120 minutes thereafter.

[0030] A physiological saline solution, a 0.005 w/v % latonoprostaqueous solution (latanoprost), a 0.25 w/v % nipradilol aqueous solution(nipradilol), a combination of latanoprost and nipradilol (Example 1),and a combination of a 0.5 w/v % indomethacin aqueous solution(indomethacin), latonoprost, and nipradilol were used as the eye dropsolutions.

[0031] When nipradilol and latanoprost were used in combination,nipradilol was administered first and latanoprost was administered fiveminutes thereafter. Furthermore, when indomethacin was used, theindomethacin was administered five minutes before the administration ofnipradilol. The results are shown in Table 2, wherein the ocular tensionchange (mmHg), the change in ocular tension after administration, isshown as the mean value ± the standard error. TABLE 2 No. of Oculartension change (mmHg) Eye drop solution specimens 60 minutes 120 minutesPhysiological saline 6 24.8 ± 1.7 16.2 ± 1.6 solution Latanoprost 6 22.7± 1.2  9.8 ± 1.9 Nipradilol 6 14.7 ± 1.7*  7.3 ± 1.6* Nipradilol +Latanoprost 6  5.3 ± 3.3**^(♯♯b)  1.7 ± 2.7**^(♯) (Example 1)Indomethacin + 6 13.3 ± 3.7*^(♯)  8.2 ± 1.7* Nipradilol + Latanoprost

Test Example 2

[0032] Domesticated rabbits intravitreously administered with 100 μl ofa 5 w/v % hypertonic saline solution were used as ocular hypertensionmodels. After intravitreously administering the hypertonic salinesolution, 50 μl of each of the eye drop solutions was administered, andthe ocular tension was measured 60 and 120 minutes thereafter.

[0033] A 0.1 w/v % sodium nitroprusside aqueous solution (sodiumnitroprusside), a combination of the sodium nitroprusside and a 0.005w/v % latanoprost aqueous solution (latanoprost) (Example 2) and acombination of a 0.5 w/v % indomethacin aqueous solution (indomethacin), latanoprost, and sodium nitroprusside were used as the eye dropsolutions.

[0034] When sodium nitroprusside and latanoprost were used incombination, sodium nitroprusside was administered first and latanoprostwas administered five minutes thereafter. Furthermore, when indomethacinwas used, the indomethacin was administered five minutes beforeadministration of sodium nitroprusside. The results are shown in Table3, wherein the ocular tension reduction (mmHg), the change in oculartension after administration, is shown as the mean value ± the standarderror. TABLE 3 No. of Ocular tension reduction (mmHg) Eye drop solutionspecimens 60 minutes 120 minutes Sodium nitroprusside 5 18.0 ± 2.4   9.4 ± 2.5 Sodium nitroprusside + 5  4.8 ± 3.9  −2.8 ± 1.3**latanoprost (Example 2) Indomethacin + sodium 5 22.8 ± 2.9^(##)   12.4 ±6.3^(##) nitroprusside + latanoprost

[0035] The results of the above Test Examples 1 and 2 show that thecombination of the NO donating compound and prostaglandin compoundsignificantly suppresses an increase in ocular tension when comparedwith the case where these compounds are individually used. The effect ofthis combination disappeared with the addition of indomethacin. Thissuggests that the effect of preventing an increase in ocular tensionpossessed by the combination of the NO donating compound and latanoprostis a result of cycloxygenase activation. The strengthened production ofvarious endogenic prostaglandins resulting from a synergistic effect ofthe endogenic arachidonic acid derivative produced by the activation ofphospholipase A2 by latanoprost and the activation of cycloxygenase byNO is believed to have stimulated production of PGE₂, which is known tobe effective for ocular tension reduction in domesticated rabbits.

INDUSTRIAL APPLICABILITY

[0036] A medicine comprising a combination of a prostaglandin compoundand NO donating compound significantly suppresses an increase in oculartension when compared to the compounds used individually.

[0037] Therefore, the medicine of the present invention is effective intreating persons affected by ocular hypertension and glaucoma.

1. A medicine comprising a prostagland in compound and a NO donatingcompound.
 2. The medicine of claim 1, wherein the prostagland incompound is a prostaglandin F₂α derivative.
 3. The medicine of claim 1or claim 2, wherein one or more prostaglandin compounds are selectedfrom the group consisting of prostagladin F₂α, latanoprost, andisopropyl unoprostone.
 4. The medicine of any one of claims 1 through 3,wherein the NO donating compound is nipradilol.
 5. The medicine of anyone of claims 1 through 4 used for the treatment and/or prevention ofocular hypertension.
 6. The medicine of any one of claims 1 through 4used for the treatment and/or prevention of glaucoma.
 7. The medicine ofany one of claims 1 through 6 in the form of an eye drop solution.
 8. Amedicine kit comprising a preparation of a prostaglandin compound and apreparation of a NO donating compound.
 9. The medicine kit of claim 8used for the treatment and/or prevention of ocular hypertension.
 10. Themedicine kit of claim 8 used for the treatment and/or prevention ofglaucoma.